Project Summary Cardiac arrest remains one of the leading causes of death and disability in the U.S.A. This proposal is a competitive renewal application. In the previous funding cycle, we defined the pathophysiological mechanisms impairing functional recovery following asphyxia cardiac arrest (ACA). Because CA promotes significant cognitive deficits, our central emphasis in the previous cycle was to understand the mechanisms behind ACA induced synaptic deficits and to establish novel, mitigating therapies against these deficits. Furthermore, new evidence in heart failure (HF) patients indicate that brain alterations in these patients are similar to regions affected by Alzheimer's disease (AD), suggesting that HF may be a major risk factor for AD. We discovered, in our previous studies, that physical exercise (PE) following ACA significantly enhances cognitive recovery. To require ailing, elderly CA patients, however, to adhere to a chronic exercise regimen presents a major obstacle. Therefore, we focus this competitive renewal on defining the mechanisms by which PE ameliorates cognitive deficits following ACA, and specifically defining potential post-ACA neurotherapeutics to act synergistically, with mild, beneficial PE. These goals will be achieved in the following specific aims: 1) To determine the effect of post-ACA PE on synaptic function, cognitive outcomes, and AD-like pathology of young female and male rats; 2) To identify molecular factors mediating the ameliorating effects of PE on cognitive deficits following ACA; and 3) To determine whether the combination of PE with pharmacological agents mitigates cognitive deficits and improves functional recovery after ACA in aged animals of both sexes.